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Enzyme and receptor modulation

a technology applied in the field of enzymes and receptors, can solve the problems of poor potency of modulators, and achieve the effect of prolonging and/or increasing activity

Inactive Publication Date: 2010-12-16
CHROMA THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006]As in the case of WO 2006 / 117567, the present invention makes use of the fact that there are carboxylesterase enzymes within cells, which may be utilised to hydrolyse an α,α-disubstituted glycine ester motif attached to a given modulator to the parent acid. Therefore, a modulator may be administered as a covalent conjugate with an α,α-disubstituted glycine ester, in which form it readily enters the cell where it is hydrolysed efficiently by one or more intracellular carboxylesterases, and the resultant α,α-disubstituted glycine-modulator conjugate accumulates within the cell, increasing overall potency and / or active residence time. It has also been found that by modification of the α,α-disubstituted glycine ester motif or the way in which it is conjugated, modulators can be targeted to monocytes and macrophages. Herein, unless “monocyte” or “monocytes” is specified, the term macrophage or macrophages will be used to denote macrophages (including tumour associated macrophages) and / or monocytes.

Problems solved by technology

The potencies of the modulators are therefore poor despite their high binding affinities for the target enzyme or receptor.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

examples 1-6

[0093]The compounds 6-amino-5-(2,4-difluoro-benzoyl-1-phenyl-1H-pyridin-2-one (Compound I) and 6-amino-5-(2,4-difluoro-benzoyl-1-(2,5-difluorophenyl-1H-pyridin-2-one (Compound H):

are known inhibitors of the intracellular enzyme p38 MAP kinase (WO 03 / 076405). Examples 1, 3 and 5 below relate to the covalent conjugation of esterase motifs with di-substitution at the alpha carbon of the amino acid ester to these compounds, in a position remote from the binding interface between the inhibitor and the target enzyme (see the comments above concerning the binding mode of a model p38 MAP kinase inhibitor). Examples 2, 4 and 6 below relate to the carboxylic acid esterase hydrolysis products of Examples 1, 3 and 5 respectively.

Synthesis of Examples 1-6

Intermediate 1: 4-Chlorophenyl 3-(2,4-difluorophenyl)-3-oxopropanimidothioate

[0094]

[0095]Intermediate 1 can be prepared using experimental procedures described in WO 2003076405.

Intermediate 2: {4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2...

example 1

Cycopentyl N-(2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}ethyl)-2-methylalaninate

[0134]

[0135]In this example compound of the invention, a dimethyl glycine cyclopentyl ester motif is covalently conjugated to the parent p38 MAP kinase inhibitor via the amino group of the dimethyl glycine cyclopentyl ester and through a —CH2CH2— linker radical.

[0136]The compound was synthesised using Intermediate 2 and Intermediate 3 as described below.

[0137]To a solution of Intermediate 2 (189 mg, 0514 mmol) in anhydrous THF (4 mL) were added cyclopentyl 2-methylalaninate hydrochloride (Intermediate 3) (160 mg, 0.77 mmol, 1.5 eq) and NaBH(OAc)3 (326 mg, 1.54 mmol, 3 eq). The mixture was stirred at room temperature for 16 hours, and then quenched with water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL), and the combined organic extracts washed with brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by prepa...

example 2

N-(2-{4-[6-Amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}ethyl)-2-methylalanine

[0139]

[0140]This Example relates to the carboxylic acid hydrolysis product of the compound of Example 1.

[0141]The compound was synthesised using Intermediate 2 and Intermediate 4 as described below in Scheme 6.

Stage 1-tert-Butyl N-(2-{-4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]phenyl}ethyl)-2-methylalaninate

[0142]To a solution of Intermediate 2 (180 mg, 0.489 mmol) in THF (3 mL) was added tert-butyl 2-methylalaninate (Intermediate 4) (117 mg, 0.73 mmol), stirred for 30 minutes, and then NaBH(OAc)3 (310 mg, 1.467 mmol). The reaction was stirred for 24 hours, diluted with EtOAc and the organic washed with sat NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound (120 mg, 48% yield).

[0143]LC / MS: m / z 512 [M+H]+. 1H NMR (300 MHz, CDCl3) δ: 10.41 (1H, br s), 7.51-7.34 (4H, m), 7.28-7.26 (2H, m), 7.05-6.90 (2...

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Abstract

Covalent conjugates of an α,α-disubstituted glycine ester and a modulator of the activity of a target intracellular enzyme or receptor, wherein the ester group of the conjugate is hydrolysable by one or more intracellular carboxylesterase enzymes to the corresponding acid and the α,α-disubstituted glycine ester is conjugated to the modulator at a position remote from the binding interface between the inhibitor and the target enzyme or receptor pass into cells and the active acid hydrolysis product accumulates within the cells.

Description

[0001]This invention relates to a general method of increasing or prolonging the activity of a compound which modulates the activity of an intracellular enzyme or receptor by the covalent conjugation of an α,α-disubstituted glycine ester motif to the modulator. The invention also relates to modulators to which an α,α-disubstituted glycine ester motif has been covalently conjugated, and to a method for the identification of such conjugates having superior properties relative to the parent non-conjugated modulator. The invention further relates to the use of modulators containing α,α-disubstituted glycine ester motifs that allow the selective accumulation of amino acid conjugates inside cells of the monocyte-macrophage lineage.BACKGROUND TO THE INVENTION[0002]Many intracellular enzymes and receptors are targets for pharmaceutically useful drugs which modulate their activities by binding to their active sites. Examples appear in Table 1 below. To reach the target enzymes and receptors,...

Claims

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Application Information

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IPC IPC(8): C07D213/56C07D213/79C07C229/48C07C229/34A61K31/4418A61K31/216A61K31/196A61K31/197A61K31/44G01N33/566A61P35/00A61P37/02A61P29/00
CPCA61K47/48038C12Q1/485C07D213/73A61K47/542A61K31/4418A61P29/00A61P35/00A61P37/02A61P43/00A61K47/50A61K47/30
Inventor DAVIDSON, ALAN HORNSBYDRUMMOND, ALAN HASTINGSMOFFAT, DAVID FESTUS CHARLESDONALD, ALISTAIR DAVID GRAHAMDAVIES, STEPHEN JOHN
Owner CHROMA THERAPEUTICS
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